ARC Journal of Surgery

Volume 5, Issue 1, 2019, PP 27-31

ISSN 2455-572X
DOI: http://dx.doi.org/10.20431/2455-572X.0501005
www.arcjournals.org

Local Therapy Modalities in Management of Colorectal Cancer

Liver Metastasis
Yusuf Sevim, Assoc. Prof*, Ibrahim Burak Bahcecioglu, M.D, Sedat Carkit, M.D
Kayseri City Hospital, Department of General Surgery, Kayseri, Turkey

*Corresponding Author: Yusuf Sevim, Assoc. Prof., Kayseri City Hospital, Department of General Surgery,
Seker Mahallesi, 38080 Molu, Kocasinan / Kayseri / Turkey, E-mail: yusufsevim@gmail.com

Abstract: Liver is the most common site of metastasis in colorectal cancers, and metastatic liver disease is
found nearly 25% of the patients at diagnosis. Additionally, liver metastasis occurs in approximately half of
the cases during the course of the disease. Liver metastases are important in colorectal cancer morbidity and
mortality. So, management of liver metastases of colorectal cancer is important. Recently, many treatment
modalities have been introduced in addition to surgery. Liver-directed therapies increase treatment options
and improve outcomes in metastatic disease. In this paper, we reviewed and summarized these treatment
options in patients with colorectal liver metastases.
Keywords: Colorectal cancer; liver; metastasis.

1. INTRODUCTION disease (excluding portal lymphadenopathy),

Colorectal cancers (CRC) are the third leading
cause of cancer-related mortality in both
genders in the United States [1]. In 2019, an
estimated 145,600 adults will be diagnosed with
CRC [1]. Up to 25% of CRC admit initially with
colorectal liver metastasis (CRLM), and
approximately 50% develop CRLM during the
course of the disease. The stage 4 CRC has the
lowest 5-year survival rates; 12 % for colon
cancer, 13% for rectal cancer. Liver
metastasectomy may improve overall survival,
and these patients may have long-term relapse
free survival. So the management of liver
metastasis becomes more important. The local
liver therapies can expand the options of
management and improve outcomes for CRLM
patients.
2. SURGERY
There is no definite definition for resectable
CRLM. Ekberg and colleagues reported
traditionally resectability criteria as 4
intrahepatic metastases, no extrahepatic
metastatic disease and being able to achieve at
least 1 cm resection margin [2]. However, liver
3-dimensional reconstruction imaging
technology, portal vein embolization, and
associated liver partition and portal venous
ligation for staged hepatectomy can increase the
resectability. So, current resectability criteria are
stable or resectable extrahepatic metastatic
amen able to venous resection or reconstruction,
beyond 1 mm with a tumor-free margin, >20%
remnant liver for normal liver and slight
chemotherapy-associated liver dysfunction and
>30-40% for severe chemotherapy-associated
liver disease [3]. The number and distribution of
liver metastasis are not decisive for resectability.
Preoperative imaging procedures, such as
computed tomography (CT), magnetic
resonance imaging and positron emission
tomography-CT are helpful to evaluate
resectability. Especially CT is optimal to
evaluate the relation between metastatic mass
and vascular, biliary structures, and to identify
the volume of remnant liver. Requiring resection
of all hepatic veins, both portal veins, or the
retrohepatic vena cava to achieve negative
margins are considered unresectable, and also
the resection of liver metastasis should not
advised in the presence of unresectable
extrahepatic disease [4].
Surgery can be performed in synchronous
CRLM with 3 surgical strategies. The first is
known classic or bowel first technique include
removal of primary colorectal tumor, followed
by chemotherapy and 3-6 months later with
resection of metastatic lesion. In combined
technique, resection of the primary tumor and
metastatic liver lesion are performed together.
The last technique is known as liver first
technique and involves resection of liver

ARC Journal of Surgery Page |27

Local Therapy Modalities in Management of Colorectal Cancer Liver Metastasis
metastasis followed by chemotherapy and
removal of the primary tumor [4].
The only curative treatment option in isolated
CRLM is combination of hepatic resection with
systemic therapy. However, this combination is
curative in only 20% of the patients, and disease
recurrence primarily to the liver is occurred in
approximately 70% of the patients after
resection [5, 6].
2.1. Biological Targeted Therapy and
Chemotherapy
Biological targeted therapy and chemotherapy
are used to reduce metastatic disease in cases of
unresectable CRLM and delay the progression.
The chemotherapy can be administered as
adjuvant or neoadjuvant for initially resectable
CRLM. However there are not enough data that
adjuvant chemotherapy improves overall
survival [7]. In the EORTC 40983 trial, the
researchers compared overall survival between
perioperative chemotherapy group with
leucovorin, 5-fluorouracil, and oxaliplatin
(FOLFOX) and surgery alone group, and there
were no statistically significant differences [8].
Data show us clinicians should avoid using
preoperative chemoradiotherapy, but
chemotherapy may be used to downstage
CRLM for parenchymal preserving resection
[9].
Combination of chemotherapy with biological
agents targeting vascular endothelial growth
factor (bevacizumab) or epidermal growth factor
receptor (cetuximab) are recommended for
unresectable CRLM in NCCN guidelines with
the aim of conversion to resection [10]. The
phase 2 CELIM trial evaluated cetuximab
combination with FOLFOX or leucovorin,
fluorouracil, and irinotecan (FOLFIRI) in
unresectable CRLM and 34% of the cases
included in this study achieved to undergo
complete resection of liver metastasis [11].
Additionally, the phase 2 OLIVIA trial
evaluated bevacizumab with modified
FOLFOX-6, or leucovorin, 5-fluorouracil,
oxaliplatin, and irinotecan (FOLFOXIRI) in
unresectable CRLM. This study showed
significantly higher overall tumor response rate,
and complete resection rates in bevacizumab-
FOLFOXIRI group. However, grade 3 or higher
adverse events such as neutropenia, diarrhea,
and febrile neutropenia were seen 95% of
bevacizumab-FOLFOXIRI group, and 84% of
bevacizumab-mFOLFOX-6 group [12].
ARC Journal of Surgery
2.2. Radiofrequency and Microwave Ablation
The standard local treatment method for CRLM
is resection, but oligometastatic cases can be
considered for radiofrequency ablation (RFA).
This is the most widely used non-surgical
technique in CRLM [13]. The use RFA is a
reasonable treatment option for non-surgical
candidates. Shady and colleagues published the
results of 162 patients with 233 CRLMs treated
with RFA, and the method was found successful
in 94% of the cases [14]. In this study,
progression-free survival and overall survival
were found 26 and 36 months respectively, and
tumor size larger than 3 cm and more than 1
extrahepatic disease were the independent
predictors of shorter overall survival [14]. Also,
randomized phase 2 EORTC 40004 trial
compared FOLFOX +/- bevacizumab (systemic
treatment alone) and systemic treatment with
RFA (combined modality), and there were no
difference in overall survival initially, but
prolonged follow-up showed improved overall
survival in combined group. Additionally,
progression-free survival was improved at 3
years in the RFA group [15]. Kwanet. al
evaluated a total of 63 CRLM patients (109
tumors) treated with RFA, and they identified
that average tumor-free survival was 14.4 ± 1.4
months (range, 1-43 months), and local
recurrence was occurred in 31.2% of treated
tumors (34/109) [16].
Microwave ablation is another technique for
ablation that is used for particularly small
metastases in CRLM. There is an ongoing
prospective, randomized, phase 3 COLLISION
trial comparing surgery versus ablation modality
(RFA or microwave ablation) in 618 patients
with 3 cm or less CRLM, and the primary
endpoint is overall survival [17]. Ablation alone
or in combination with surgical resection should
be chosen in CRLM patients especially who are
not optimal candidates for resection.
2.3. Radioembolization
Radioembolization is a minimally invasive
method include both embolization and radiation
therapy to treat liver cancer. The radioactive
isotope yttrium 90 (Y-90) is used in this
procedure. Also, this method can be named as
transarterial radioembolization, internal
radiation therapy, and intra-arterial
brachytherapy. Generally Y-90 radioemboli
zation is suggested in chemotherapy resistant or
refractor cases with predominant liver
metastasis (18). Radioembolization with chemot
herapycan lengthen time to progression in
CRLM [19].
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Local Therapy Modalities in Management of Colorectal Cancer Liver Metastasis
The phase 3 randomized controlled SIRFLOX
trial (Y-90 resin microspheres with FOLFOX+/-
bevacizumab vs. FOLFOX+/- bevacizumab) results
showed significant prolonged progression-free
survival in FOLFOX/Y-90 group (20.5 vs. 12.6
months) [20]. Additionally, the FOXFIRE and
FOXFIRE Global studies showed prolonged
progression-free survival similar with SIRFLOX
trial [21]. Radioembolization with low systemic
toxicity is a feasible treatment option for
chemotherapy refractor unrespectable CRLM
cases.
2.4. Hepatic Artery Infusion Therapy
Treatment with liver-directed chemotherapy
through hepatic arterial infusion (HAI), besides
systemic chemotherapy, is a method that can be
used to downsize the disease in the liver with
the aim of conversion to surgical resection [22].
This procedure is administered in the
gastroduodenal artery by surgically implanted
pump, hepatic artery port, or through a catheter
connected to an external pump placed
percutaneously. HAI provides less systemic
toxicity. The clinicians should choose the
chemotherapeutic agent for HAI in order to
increase the local concentration, which increases
therapeutic response and to decrease the
systemic exposure. Floxuridine has short half-
life and high first-pass metabolism rate, so it is
the most widely used agent [23]. Also irinotecan
[24] and oxaliplatin [25] have been used for
intrahepatic infusion. Additionally, some
investigators used irinotecan, oxaliplatin and
floxuridine by HAItogether with systemic
chemotherapy as first-line treatment of
unresectable liver metastasis [26].
Floxuridine may cause diarrhea or gastric and
duodenal ulcers because of extrahepatic
profusion, and the common side effect is biliary
toxicity. So that, the clinicians should monitor
liver function tests every 2 weeksto adjust the
dose of floxuridine [23]. Biliary toxicity of
floxuridine can be decreased with combination
of dexamethasone. Also using fluorouracil
alternatively is a way to prevent biliary toxicity
[27, 28].
HAI with floxuridine alone may increase the
objective responses compared to systemic
chemotherapy with floxuridine or 5-flourouracil
[29]. Fiorentini et. Al compared HAI combination
with bolus 5-flourouracil/leucovorin or HAI alone,
and they identified an increase in survival in the
combined group (20 vs. 14 months, p=0.0033)
[30].
ARC Journal of Surgery
In unrespectable CRLM, the only randomized
comparison of HAI versus systemic
chemotherapy is the phase 3 CALGB 9481 trial
[31]. This trial showed that, improved median
survival (24.4 vs. 20 months, p=0.0034) and
objective response rate (47 vs. 24%, p=0.12)
was associated with HAI. This trial also
identified the toxicity status, and the common
toxicity was biliary toxicity (Bilirubin elevation
>3mg/dL; 18.6 vs. 0%, p=0.006). Combination
of HAI with systemic chemotherapy is used to
achieve conversion to complete resection of
liver metastasis. In the phase 2 MSKCC trial
initial report [5] and expansion cohort [32]
demonstrated 47% and 52% conversion to liver
metastasis respectively. Additionally adjuvant
HAI after resection of CRLM has been shown to
delay hepatic recurrence [33].
There are some possible complications of HAI
therapy. These are hemorrhage, thrombosis,
extrahepatic perfusion, incomplete perfusion as
arterial complications, infection, hematoma,
pump migration as pocket complications, and
occlusion, dislodgement, erosion, pump
malfunction as catheter complications. Also
biliary sclerosis is a rare important complication
associated with abnormal postoperative flow
scans, postoperative infectious complications,
and larger doses of floxuridine per cycle [34].
3. CONCLUSION
Improving treatment modalities in CRLM
provide options to clinicians with improving
clinical outcomes. Surgical resection of CRLM
is curative approximately in 20% of patients, so
that these local treatment modalities become
more important especially in unrespectable
CRLM. Some of these potentially improve
overall survival or progression-free survival.
More studies, clinical trials are required for
unrespectable CRLM.
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Citation: Yusuf Sevim, Ibrahim Burak Bahcecioglu, Sedat Carkit. Local Therapy Modalities in Management
of Colorectal Cancer Liver Metastasis. ARC Journal of Surgery.2019; 5(1):27-31. DOI: http://dx.doi.org/10.2
0431/2455-572X.0501005
Copyright: © 2019 Authors. This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
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